WO2016074651A1 - Procédé de préparation, d'isolation et de purification de formes pharmaceutiquement applicables de ahu-377 - Google Patents

Procédé de préparation, d'isolation et de purification de formes pharmaceutiquement applicables de ahu-377 Download PDF

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WO2016074651A1
WO2016074651A1 PCT/CZ2015/000136 CZ2015000136W WO2016074651A1 WO 2016074651 A1 WO2016074651 A1 WO 2016074651A1 CZ 2015000136 W CZ2015000136 W CZ 2015000136W WO 2016074651 A1 WO2016074651 A1 WO 2016074651A1
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ahu
crystalline
salt
formula
salts
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PCT/CZ2015/000136
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English (en)
Inventor
Ales Halama
Pavel ZVATORA
Ondrej Dammer
Jan Stach
Michal Zapadlo
Lukas KREJCIK
Michal Voslar
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Zentiva, K.S.
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Priority claimed from CZ2014-792A external-priority patent/CZ2014792A3/cs
Priority claimed from CZ2015-758A external-priority patent/CZ2015758A3/cs
Application filed by Zentiva, K.S. filed Critical Zentiva, K.S.
Priority to LTEP15808087.9T priority Critical patent/LT3218351T/lt
Priority to PL15808087T priority patent/PL3218351T3/pl
Priority to ES15808087T priority patent/ES2745157T3/es
Priority to EP15808087.9A priority patent/EP3218351B1/fr
Priority to DK15808087.9T priority patent/DK3218351T3/da
Publication of WO2016074651A1 publication Critical patent/WO2016074651A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C233/00—Carboxylic acid amides
    • C07C233/01—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms
    • C07C233/45—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups
    • C07C233/46—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom
    • C07C233/47—Carboxylic acid amides having carbon atoms of carboxamide groups bound to hydrogen atoms or to acyclic carbon atoms having the nitrogen atom of at least one of the carboxamide groups bound to a carbon atom of a hydrocarbon radical substituted by carboxyl groups with the substituted hydrocarbon radical bound to the nitrogen atom of the carboxamide group by an acyclic carbon atom having the carbon atom of the carboxamide group bound to a hydrogen atom or to a carbon atom of an acyclic saturated carbon skeleton
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/02—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C211/03—Monoamines
    • C07C211/06—Monoamines containing only n- or iso-propyl groups
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/01—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms
    • C07C211/02—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to acyclic carbon atoms of an acyclic saturated carbon skeleton
    • C07C211/03—Monoamines
    • C07C211/07—Monoamines containing one, two or three alkyl groups, each having the same number of carbon atoms in excess of three
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07C—ACYCLIC OR CARBOCYCLIC COMPOUNDS
    • C07C211/00—Compounds containing amino groups bound to a carbon skeleton
    • C07C211/33—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings
    • C07C211/34—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of a saturated carbon skeleton
    • C07C211/35—Compounds containing amino groups bound to a carbon skeleton having amino groups bound to carbon atoms of rings other than six-membered aromatic rings of a saturated carbon skeleton containing only non-condensed rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07B—GENERAL METHODS OF ORGANIC CHEMISTRY; APPARATUS THEREFOR
    • C07B2200/00—Indexing scheme relating to specific properties of organic compounds
    • C07B2200/13—Crystalline forms, e.g. polymorphs

Definitions

  • the compound AHU-377 chemically (2i?,45)-5-(biphenyl-4-yl)-4-[(3-carboxypropionyl)- amino]-2-methylpentanoic acid ethyl ester of formula (1), also known as sacubitril, is a constituent of a drug for the treatment of hypertension and heart failure. It is especially the crystalline supramolecular complex of the sodium salt of AHU-377 and the disodium salt of valsartan of formula (2) in the 1: 1 ratio of the components, which crystallizes in the pentahemihydrate form (WO2003/059345 and WO2007/056546), that is of therapeutic use.
  • This supramolecular complex has been approved by the Food and Drug Administration (FDA) for the treatment of hypertension and heart failure.
  • FDA Food and Drug Administration
  • the invention relates to new solid forms of the compound referred to as AHU-377, a new method of isolation and purification of these forms, incl. a method of obtaining solid forms of AHU-377, applicable for the production of drugs for treatment of hypertension and heart failure.
  • the final step of chemical synthesis leading to AHU-377 is represented by the reaction running in accordance with Scheme 1, wherein the amine (3) reacts with succinic acid anhydride (EP555175, J. Med. Chem. 1993 ⁇ 4 38, 1689-1700).
  • the reaction results in crude AHU-377 in the free carboxylic acid form.
  • a disadvantage of this procedure is the fact that AHU-377 in the free carboxylic acid form does not crystallize and therefore this form is not suitable for isolation or for chemical purification before the preparation of the sodium salt of AHU-377, which is used as a 5 pharmaceutically acceptable form in practice (WO2007/056546).
  • the present invention represents a nj w, highly efficient and industrially usable method of isolation and purification of AHU-377 ; based on crystalline salts of AHU-377 with amines.
  • the invention is based on finding well crystallizing forms of AHU-377 that are easy to isolate and chemically purify, subsequently! converting them to pharmaceutically acceptable solid forms, especially the sodium and calcium salts of AHU-377.
  • Preparation refers to chemical transformation, purification as well as isolation of the desired substance.
  • Solid forms of AHU-377, especially the crystalline ones, can be of great technological and economical significance as they make it possible to obtain a substance applicable for pharmaceutical purposes.
  • Chemical synthesis of AHU-377 leads to the free crude carboxylic acid of an oily character (see Scheme 1), which is difficult to isolate in the pure form, it being the consequence of its inability to crystallize.
  • the invention relates to a new and efficient method of isolation and purification of AHU-377, wherein a solution of the AHU-377 carboxylic acid is treated with a suitable amine to provide a solution of salts of AHU-377 with amines (9). It has been found out that only some suitable salts of AHU-377 crystallize surprisingly easily, especially with the amines specified below, which can thus be conveniently isolated from the solution in a solid and chemically pure form.
  • the invention further relates to a convenient method of removal of chemical impurities by repeated crystallizations of salts of AHU-377 with certain amines and a to new preparation method of the amorphous form of the sodium salt, crystalline or semicrystalline calcium salt of AHU-377 using a direct transformation of the salts of AHU-377 with amines by the procedure in accordance with Scheme 5. It has been experimentally found out that a good crystallization capability of amine salts of AHU-377 is not a general characteristics of these salts.
  • the salts of AHU-377 with the following amines have proved their ability to crystallize well and to improve the quality of the isolated substances: ieri-butylamine, iso-propylamine, cyclohexylamine, ⁇ -propylamine and ⁇ cyclohexylamine.
  • the formerly described salts with triethanolamine (7) and tris(hydroxmethyl)aminomethane (8) can also be obtained in a crystalline form, but their purification ability is worse, as shown in Table 1.
  • R 2 and R 3 independently mean a d-C 6 alkyl or hydrogen
  • the first step represents chemical synthesis of AHU-377, especially the final reaction of the amine (3) with succinic acid anhydride in accordance with Scheme 5.
  • the output of this step is crude AHU-377 acid, which also contains undesired constituents such as residual solvents and residues of reactants, mainly derivatives of succinic acid.
  • the product of the first step, which failed to be obtained in a solid form, usually contained 97.5 to 98.5 % of the target compound according to HPLC analyses.
  • the second step represents isolation of AHU-377 in the form of solid, well crystallizing salts of AHU-377 with amines (9). Preparation of these salts consists in dissolution of AHU-377 acid in at least one organic solvent, adding of a suitable amine to the solution, agitation of the mixture, filtration of the separated solid form and drying of the isolated substance.
  • the output of this step is a crystalline form of a salt of AHU-377 with an amine that is characterized by a higher chemical purity as compared to the input AHU-377 acid.
  • Crystalline salts of AHU-377 with primary amines selected from the group of tert-butylamine, iso-propylamine and cyclohexylamine especially offer convenient crystallizing characteristics, which are associated with the crystal structure of these salts. These salts have been found out to provide stable crystal forms that can be unambiguously characterized by means of X-ray powder diffraction (XRPD, see analytic methods and annexes). The contribution of the discovered process of purification of AHU-377 in the form of its salts with amines is an exceptionally good ability of these salts to crystallize from solutions of organic solvents, which leads to increased chemical purity of the isolated substance.
  • XRPD X-ray powder diffraction
  • Organic solvents usable for isolation of salts of AHU-377 with amines can be selected from the group: esters of C1-C5 organic acids with C1-C6 alcohols, C1-C6 alcohols, C3-C6 ketones, C4-C6 ethers, C1-C6 chlorinated hydrocarbons, liquid aromatic hydrocarbons, C1-C7 alkanes, C1-C7 cycloalkanes.
  • solvents or their mixtures are especially suitable: ethyl acetate, isopropyl acetate, methanol, ethanol, iso-propyl alcohol, acetone, methyl ethyl ketone, diethyl ether, tefrahydrofuran, 2-methyltetrahydrofuran, ieri-butyl methyl ether, dichloromethane, toluene, xylenes, hexane, heptane, cyclohexane.
  • the best results were achieved with ethyl acetate or wopropyl acetate.
  • An especially convenient method of isolation of a salt of an amine with AHU-377 is one where steps 1 and 2 are joined together, i.e. a method that does not require isolation of AHU- 377 acid.
  • This modification is characterized by isolation of the salt of AHU-377 with a primary amine directly from the reaction environment used for performing step 1. In this case, the mixture does not have to be concentrated after the initial reaction and then the crude AHU- 377 acid does not need to be dissolved in another solvent, see Example 4.
  • the third step is crystallization of the salt of AHU-377 with an amine (9) from at least one organic solvent to further increase the chemical purity, wherein the obtained substance exhibits a higher HPLC purity than 99.5%, the contents of individual impurities being less than 0.1%.
  • This step represents the final removal of chemical impurities.
  • the output of this step is a chemically pure crystalline salt of AHU-377 with an amine in a pharmaceutically acceptable quality.
  • Organic solvents usable for crystallization of salts of AHU-377 with amines can be selected from the group: esters of C1-C5 organic acids with C1-C6 alcohols, C1-C6 alcohols, C3-C6 ketones, C4-C6 ethers, C1-C6 chlorinated hydrocarbons, liquid aromatic hydrocarbons, C1-C7 alkanes, C1-C7 cycloalkanes.
  • solvents or their mixtures are especially suitable: ethyl acetate, /so-propyl acetate, methanol, ethanol, z ' so-propyl alcohol, acetone, methyl ethyl ketone, diethyl ether, tetrahydrofuran, 2-methyltetrahydrofuran, ieri-butyl methyl ether, dichloromethane, toluene, xylenes, hexane, heptane, cyclohexane.
  • the best results were achieved with ethyl acetate or zsopropyl acetate.
  • Step 4 Conversion of salts of AHU-377 with amines to salts of AHU-377 with metals
  • the last step relates to the process of conversion of crystalline salts of AHU-377 with amines (9) to a pharmaceutically acceptable salt with a metal.
  • the source of the metal can be the respective inorganic and organic salts, alcoholates or hydroxides of these metals.
  • a pharmaceutically acceptable form of AHU-377 is the sodium or calcium salt.
  • the output of this step is an active pharmaceutical substance (API) usable for the preparation of a drug for the treatment of hypertension and heart failure.
  • API active pharmaceutical substance
  • a convenient aspect of preparation of the amorphous form of the sodium salt of AHU-377 is a direct conversion of salts of AHU-377 with amines to this form, which has not been described yet.
  • the discovered method of preparation of the amorphous form of the sodium salt of AHU- 377 is especially convenient through the use of crystalline and chemically pure salts of AHU- 377 with primary amines, which, compared to secondary amines, are characterized by lower basicity and sufficient volatility, which enables efficient removal of the primary amine without undesired contamination of the product during the preparation of the sodium salt of AHU-377.
  • crystalline salts of AHU-377 with primary amines can be conveniently used for the preparation of a crystalline or semicrystalline form of the calcium salt of AHU-377.
  • This invention provides especially processes concerning the performance of isolation and chemical purification of AHU-377, i.e. steps 2 and 3. It further provides processes of preparation of the amorphous form of the sodium salt, crystalline and semicrystalline form of the calcium salt of AHU-377, which are based on using the salts of AHU-377 with amines, i.e. step 4.
  • the newly discovered crystalline forms of AHU-377 with amines and the method of conversion of these forms to salts of AHU-377 with metals can be conveniently applied in the industrial scale and a pharmaceutical substance complying with stringent quality criteria can be effectively obtained.
  • salts of AHU-377 with alkali metals (10), or alkaline earth metals (11) can be alternatively obtained from the re-released free acid of AHU-377 (1), which is converted to the salts of (10) or (11) in organic solvents by the action of suitable agents.
  • a suitable source of the metal can be the respective alcoholates, preferably sodium methoxide, potassium methoxide, sodium ethoxide, potassium ethoxide, sodium iso-propoxide, potassium iso-propoxide, soidum tert-butoxide, or potassium tert-butoxide.
  • Salts of organic acids preferably salts of organic acids soluble in organic solvents, can also be used instead of the alcoholates.
  • the sodium, potassium or calcium salts of 2-ethylhexanoic acid can be used as salts of organic acids.
  • the invention further provides pharmaceutically acceptable crystalline and semicrystalline forms of the calcium salt of sacubitril and methods for the preparation thereof.
  • These solid forms of the calcium salt of sacubitril are prepared by crystallization, precipitation or evaporation from a solution of the calcium salt of sacubitril in a suitable solvent or mixtures of solvents.
  • the invention provides crystalline form I of the calcium salt of sacubitril, exhibiting the following characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 3.6; 6.4; 14.5 and 19.6 ⁇ 0.2° 2-theta.
  • crystalline form I of the calcium salt of sacubitril is characterized by the following other reflections in the X-ray powder pattern: 8.4; 10.8; 17.7; 20.6 and 22.5 ° ⁇ 0.2° 2-theta. In some embodiments crystalline form I of the calcium salt of sacubitril is further characterized by the differential scanning calorimetry curve with the melting point at 86°C.
  • the invention further provides a method for the preparation of crystalline form I of the calcium salt of sacubitril, comprising:
  • a/ dissolution of the calcium salt of sacubitril in one of the solvents selected from the group of: ethanol, methanol, dimethyl sulfoxide, butyl acetate, acetonitrile, isopropyl alcohol, butanol acetone, or a mixture of these solvents at a temperature in the range from 25 °C to the boiling point of the solvent;
  • the invention further provides crystalline form II of the calcium salt of sacubitril, exhibiting the following characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 3.2; 7.4; 12.9; 18.7 and 22.5; ⁇ 0.2° 2-theta.
  • crystalline form II of the calcium salt of sacubitril is characterized by the following other reflections in the X- ray powder pattern: 11.4; 16.2; 23.7 and 27.1 ⁇ 0.2° 2-theta.
  • crystalline form II of the calcium salt of sacubitril is further characterized by the differential scanning calorimetry curve with the melting point at 68°C.
  • the invention further provides a method for the preparation of crystalline form II of the calcium salt of sacubitril, comprising:
  • the invention further provides semicrystalline form III of the calcium salt of sacubitril, exhibiting the following reflections in the X-ray powder pattern with the use of CuKa radiation: 4.0 and 4.7 ⁇ 0.2° 2-theta.
  • semicrystalline form III of the calcium salt of sacubitril is further characterized by the differential scanning calorimetry curve with the melting point at 124°C.
  • the invention further provides a method for the preparation of semicrystalline form III of the calcium salt of sacubitril, comprising:
  • the invention further provides semicrystalline solid form IV of the calcium salt of sacubitril, exhibiting the following characteristic reflections in the X-ray powder pattern with the use of CuKa radiation: 4.6; 6.4 and 14.3 ⁇ 0.2° 2-theta.
  • semicrystalline solid form IV of the calcium salt of sacubitril is further characterized by the differential scanning calorimetry curve with the melting point at 173°C.
  • the invention further provides a method for the preparation of semicrystalline form IV of the calcium salt of sacubitril, comprising:
  • Salts of pharmaceutically active substances generally have higher solubility and biological availability values than their corresponding forms of free acids or bases.
  • preparation of a salt by a reaction of an acid and base is a well-known method, it is always a problem to obtain the required salts in the solid phase and purity corresponding to the demands for their pharmaceutical use.
  • Biological availability greatly depends on whether a crystalline or amorphous product is obtained. An amorphous product is usually more readily soluble, it cannot often be obtained in the required quality and it is also often unstable. Conversely, compared to the amorphous form, a crystalline product is often stable, its required purity is easier to achieve and it dissolves more slowly. Mixtures of the amorphous and crystalline solid phase (semicrystalline forms) may represent a solution to the problem.
  • the present invention provides several solid forms of the calcium salt of sacubitril in a crystalline form or in a mixture of a crystalline and amorphous form. This invention prefers crystalline forms of the calcium salt of sacubitril.
  • the invention relates to solid forms of the calcium salt of sacubitril in variable molar ratios.
  • 2:1 molar ratios are preferred.
  • Solid forms of the calcium salt of sacubitril can be prepared in adequate ratios and yields with high chemical purity in a crystalline or amorphous form, or in a mixture of an amorphous and crystalline solid phase.
  • solid forms can be both anhydrous and/or non-solvated, and they can have the form of hydrates/solvates of the respective solvents.
  • novel solid forms are suitable for preparation of sacubitril with a high chemical and optical purity.
  • the preparation of the novel solid form of sacubitril consists in a reaction of the cyclohexylamine salt of sacubitril with calcium chloride in water, or in a mixture of water with a suitable organic solvent.
  • the resulting product of this reaction is recrystallized in a suitable solvent, which can be ketones, esters, ethers, amides, nitriles or organic acids, alcohols, aliphatic and aromatic hydrocarbons, chlorinated hydrocarbons, water or mixtures thereof.
  • Aliphatic C1-C4 alcohols, ethers, chlorinated solvents, water, or mixtures thereof are preferred.
  • the most frequently used solvents are ethanol, tetrahydrofuran, dioxane, chloroform, water or mixtures thereof.
  • the final product is typically precipitated or crystallized at temperatures in the range of -30°C to the boiling point of the solvent.
  • the invention prefers crystalline forms of the calcium salt of sacubitril (form I and form II), which, due to their crystalline nature, have excellent physical and chemical stability.
  • the prepared solid forms of the calcium salts of sacubitril exhibit a sufficiently high melting point, physical and chemical stability for use in a dosage form.
  • the main advantage of the calcium salts of sacubitril over the sodium salt of sacubitril is their higher physical and chemical stability during storage.
  • the calcium salt of sacubitril has been found not to change its chemical purity under the test conditions.
  • Crystalline forms of the calcium salt of sacubitril can be prepared and isolated with a high yield and high chemical purity.
  • the cyclohexyl ammonium salt of sacubitril was prepared according to the procedure presented in Example 1.
  • the calcium salt of sacubitril was prepared according to the procedure presented in Example 2. Crystalline form I of the calcium salt of sacubitril is characterized by the reflections presented in Table 2. Table 2 includes reflections whose relative intensity value is higher than 1 %. Characteristic diffraction peaks of crystalline form I of the calcium salt of sacubitril according to the present invention with the use of CuKa radiation are: 3.6; 6.4; 14.5 and 19.6 ⁇ 0.2° 2- theta. The X-ray powder pattern is shown in Fig. 8.
  • Crystalline form II of the calcium salt of sacubitril is characterized by the reflections presented in Table 3. Table 3 includes reflections whose relative intensity value is higher than 1 %. Characteristic diffraction peaks of crystalline form II of the calcium salt of sacubitril according to the present invention with the use of CuKa radiation are: 3.2; 7.4; 12.9; 18.7 and 22.5; ⁇ 0.2° 2-theta.
  • the X-ray powder pattern is shown in Fig. 9.
  • the melting point of crystalline form II of the calcium salt of sacubitril as measured by differential scanning calorimetry (DSC) was 68°C.
  • Semicrystalline form III of the calcium salt of sacubitril is characterized by the reflections presented in Table 4. Table 4 includes reflections whose relative intensity value is higher than 1 %. Characteristic diffraction peaks of semicrystalline form III of the calcium salt of sacubitril according to the present invention with the use of CuKa radiation are: 4.0 and 4.7 ⁇ 0.2° 2-theta.
  • the X-ray powder pattern is shown in Fig. 10.
  • Semicrystalline form IV of the calcium salt of sacubitril is characterized by the reflections presented in Table 5.
  • Table 5 includes reflections whose relative intensity value is higher than 1 %.
  • Characteristic diffraction peaks of semicrystalline form IV of the calcium salt of sacubitril according to the present invention with the use of CuKa radiation are: 4.6, 6.4 and 14.3 ⁇ 0.2° 2-theta.
  • the X-ray powder pattern is shown in Fig. 11.
  • the melting point of semicrystalline form IV of the calcium salt of sacubitril as measured by differential scanning calorimetry (DSC) was 173°C.
  • the solid forms of calcium salts of sacubitril prepared according to this invention can be used for the preparation of pharmaceutical compositions, especially solid dosage forms, e.g. tablets or capsules.
  • Such pharmaceutical compositions can only contain at least one excipient from the group of fillers (e.g. lactose), binders (e.g. n icrocrystalline cellulose), disintegrants (e.g. sodium salt of croscarmellose), lubricants (e.g. magnesium stearate), surfactants etc.
  • the calcium salt of sacubitril can be mixed with the above mentioned excipients, screened through a sieve and the resulting mixture can be tabletted or filled into capsules.
  • the tablets can be further coated with common coating compounds, e.g. polyvinyl alcohol or polyethylene glycol.
  • Fig. 1 XRPD pattern of crystalline salts of AHU-377 with amines, i.e. dependence of diffused light intensity on the 2-theta diffraction angle. (a) salt with /eri-butylamine
  • Fig. 2 1H NMR spectra of crystalline salts of AHU-377 with amines.
  • Fig. 3 XRPD pattern of the crystalline salt of AHU-377 (11, M stands for calcium). The pattern illustrates dependence of diffused light intensity on the 2-theta diffraction angle.
  • Fig. 4 XRPD pattern semicrystalline calcium salt of AHU-377 (11, M stands for calcium). The pattern illustrates dependence of diffused light intensity on the 2-theta diffraction angle.
  • Fig. 5 XRPD pattern of the crystalline ttis(hydroxmemyl)ammomethane salt of AHU-377 (8). The pattern illustrates dependence of diffused light intensity on the 2-theta diffraction angle.
  • Fig. 6 XRPD pattern of the amorphous sodium salt of AHU-377 (10, M stands for sodium). The pattern illustrates dependence of diffused light intensity on the 2-theta diffraction angle.
  • Fig. 7 1H NMR spectrum of the sodium salt of AHU-377 (10, M stands for sodium).
  • Fig. 8 XRPD pattern of sacubitril calcium salt crystalline Form I.
  • Fig. 9 XRPD pattern of sacubitril calcium salt crystalline Form II.
  • Fig. 10 XRPD pattern of sacubitril calcium salt semicrystalline Form ⁇ .
  • Fig. 11 XRPD pattern of sacubitril calcium salt semicrystalline Form IV. Examples The object of the invention will be clarified in a more detailed way in the following examples, which, however, do not have any influence on the invention scope defined in the claims.
  • EXAMPLE 2 (general method of preparation and isolation of a salt of AHU-377 with amines)
  • Ri, R 2 and R 3 independently mean a Ci-C 6 atkyl or hydrogen
  • AHU-377 acid (1) was dissolved in an organic solvent.
  • An amine was added to the solution in an amount corresponding to 1.1 equivalents of AHU-377.
  • the mixture was agitated.
  • the precipitated crystalline salt of the amine with AHU-377 (9) was isolated by filtration, washed with mother liquor and with the solvent used and dried in vacuo.
  • the isolated crystalline salts were characterized by means of X PD, the structure was verified with the use of 1H N R and the chemical purity with the use of HPLC.
  • the measured values of chemical purity for the series of amines are summarized in Table 6, the results of other analyses (1H NMR, XRPD) are included below.
  • EXAMPLE 2a (method of preparation and isolation of the crystalline salt of AHU-377 with fert-butylamine)
  • AHU-377 acid (1) 1 g was dissolved in 10 ml of ethyl acetate. N-propyl amine was added to the solution in an amount corresponding to 1.1 equivalents of AHU-377. The mixture was agitated. The precipitated crystalline salt of the amine with AHU-377 (9) was isolated by filtration, washed with mother liquor and with the solvent used and dried in vacuo. The yield of the salt with was 69.8 %, the chemical purity according to HPLC was 99.5 %. The result of XRPD is presented in Table 10 and in Fig. 1 (d).
  • AHU-377 acid (1) 1 g was dissolved in 10 ml of ethyl acetate.
  • Dicyclohexylamine was added to the solution in an amount corresponding to 1.1 equivalents of AHU-377.
  • the mixture was agitated.
  • the precipitated crystalline salt of the amine with AHU-377 (9) was isolated by filtration, washed with mother liquor and with the solvent used and dried in vacuo.
  • the yield of the salt with dicyclohexylamine was 53.6%, the chemical purity according to HPLC was 98.6%.
  • the result of XRPD is presented in Table 11 and in Fig. 1 (e).
  • Ri, R z and R 3 independently mean a Ci- alkyl or hydrogen
  • R ljp 2 and 3 independently mean a Ci-C 6 alkyl or hydrogen
  • Tetrahydrofuran was added to the crystalline salt of AHU-377 with a primary amine tert- butylamine, z ' -fo-propylamine, or cyclohexylamine), the suspension was agitated and 1 equivalent of sodium ierf-butoxide was added. The mixture was stirred at the room temperature until a slightly turbid solution was obtained. Then, it was filtered and heptane was added to the clear filtrate until a turbid solution was produced. This was followed by concentration in vacuo and addition of a mixture of heptane and dichloromethane in the constituent ratio of 3:1. The turbid solution was concentrated in vacuo and the obtained suspension was agitated at the room temperature. Filtering and vacuum drying followed. The isolated amorphous sodium salt was characterized by means of XRPD (Fig. 6). The product structure was verified with the use of ⁇ NMR (Fig. 7).
  • the tert-butylammonium salt of AHU-377 (0.5 g) was stirred up in 5 ml of water and calcium chloride dihydrate dissolved in water (1 g in 5 ml of water) was added. The mixture was agitated at 50°C for 3 hours, then it was cooled down to 25°C. The precipitated crystalline product was removed by filtration and dried (0.42 g, 91%, 99.67% HPLC).
  • the tert-butylanunonium salt of AHU-377 (0.5 g) was stirred up in 10 ml of water and 10 ml of ethyl acetate. After acidification of the mixture with hydrochloric acid to pH 1 the organic phase containing the free acid of AHU-377 was separated and the mixture was evaporated in a vacuum evaporator. The evaporation product was dissolved again in 10 ml of methyl ethyl ketone and the potassium salt of 2-ethylhexanoic acid (0.35 g) was added. The mixture was agitated at 50°C for one hour f then it was cooled down to 25 °C and the precipitated potassium salt of AHU-377 was removed by filtration and dried. 0.40 g of the salt (87%, 99.65% HPLC) was obtained. -377)
  • the ieri-butylammonium salt of AHU-377 (0.5 g) was stirred up in 10 ml of water and 10 ml of ethyl acetate. After acidification of the mixture with hydrochloric acid to pH 1 the organic phase containing the . acid was separated and the mixture was evaporated in a vacuum evaporator. The evaporation product was dissolved again in 10 ml of methyl ethyl ketone and the sodium salt of 2-ethylhexanoic acid (0.31 g) was added. The mixture was agitated at 50°C for one hour, then it was cooled down to 25°C and the precipitated sodium salt of AHU-377 was removed by filtration and dried. 0.39 g of the salt (87 %, 99.85% HPLC, melt, point 159 °C - 160°C) was obtained. E HU-377)
  • the iert-butylarnmonium salt of AHU-377 (0.5 g) was stirred up in 10 ml of water and 10 ml of ethyl acetate. After acidification of the mixture with hydrochloric acid to pH 1 the organic phase containing the acid was separated and the mixture was evaporated in a vacuum evaporator. The evaporation product was dissolved again in 10 ml of tetrahydrofuran and sodium methoxide (0.2 g) in methanol (1 ml) was added. The mixture was agitated at 50°C for 1 hour, then it was cooled down to 25°C and heptane (15 ml) was added and the precipitated sodium salt of AHU377 was removed by filtration and dried. 0.39 g of the amorphous salt (87%, 99.65% HPLC) was obtained.
  • the tert-butylammonium salt of AHU-377 (0.1 g) was stirred up in 2 ml of water and 2 ml of ethyl acetate. After acidification of the mixture with hydrochloric acid to pH 1 the organic phase containing the acid was separated and the mixture was evaporated in a vacuum evaporator. The evaporation product was dissolved in 2 ml of acetone and 0.243 ml of a suspension of calcium hydroxide was added that had been prepared by suspending (0.074 g) in water (1 ml). The mixture was homogenized in an ultrasonic bath and then it was left to evaporate in a vacuum drier at the room temperature. 0.113 g of the crystalline salt (96%, 98% HPLC) was obtained. The crystalline calcium salt was characterized by means of XRPD (Fig.
  • AHU-377 acid (1) 0.085 g was dissolved in ethyl acetate (2 ml) and 0.294 ml of a solution of tris(hydroxmethyl)aminomethane (0.100 g in 1 ml of water) was added. The mixture was homogenized in an ultrasonic bath and then it was evaporated in a vacuum drier at the room temperature.
  • the crystalline salt (HPLC 98.1%) was characterized by means of XRPD (Fig. 5).
  • the salt of AHU-377 with triethanolamine was prepared in an analogous way (HPLC 98.5%).
  • Example 18 Preparation of semicrystalline form III of the calcium salt of sacubitril
  • the charge of the calcium salt of sacubitril of 103.6 mg was dissolved in 0.2 ml of tetrahydrofuran in a glass vial at 66°C while being stirred in a magnetic agitator.
  • the resulting solution was evaporated in a vacuum drier at the temperature of 25 °C and the pressure of 20 kPa.
  • Example 19 Preparation of semicrystalline form IV of the calcium salt of sacubitril
  • HPLC chromatograms were measured using a UHPLC system Agilent 1290 Infinity LC.
  • Agilent 1290 Infinity LC For the analyses an ACQUITY CSH Phenyl-Hexyl; 100 mm x 3.0 mm I. D.; 1.7 ⁇ column was used.
  • As the mobile phase a mixture of acetonitnle (70 %) and HC10 4 (30 %, 1 ml of HC10 4 per 1 I of water) was used. The measurements were carried out in a gradient mode with the mobile phase flow of 0.5 ml/min at 40°C in the column.
  • Table 12 Values of characteristic diffraction angles 2 ⁇ , interpianar spacings d and relative signal intensities in the XRPD patterns of the crystalline calcium salt of AHU-377.
  • Table 13 Values of characteristic diffraction angles 2 ⁇ , interplanar spacmgs d and relative signal intensities in the XRPD patterns of the semicrystalline calcium salt of AHU-377.
  • Table 14 Values of characteristic diffraction angles 20, interplanar spacings d and relative signal intensities in the XRPD patterns of the crystalline tris(hydroxymethyl)arnino-methane salt of AHU-377 (8).
  • the records of the novel solid calcium salts of sacubitnl were measured with the Discovery DSC device made by TA Instruments.
  • the sample charge in a standard Al pot (40 ⁇ _) was between 4-5 and 5 mg and the heating rate was 5°C/min.
  • As the carrier gas 5.0 N 2 was used at the flow of 50 ml/min.

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  • Chemical & Material Sciences (AREA)
  • Organic Chemistry (AREA)
  • Organic Low-Molecular-Weight Compounds And Preparation Thereof (AREA)
  • Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Abstract

L'invention concerne un procédé d'isolation et de purification de substances dérivées de AHU-377 représenté par la formule (1), caractérisé par la transformation de la substance brute (1) en sels bien cristallisés avec des amines représentées par la formule (9) dans l'environnement d'un solvant organique approprié, puis par la recristallisation de ces sels pour éliminer simultanément les impuretés chimiques, et utiliser des sels chimiquement purs de AHU-377 avec des amines pour les transformer directement en une forme pharmaceutiquement applicable de AHU-377 avec des métaux alcalins représentés par la formule (10) ou avec des métaux alcalino-terreux représentés par la formule (11).
PCT/CZ2015/000136 2014-11-14 2015-11-11 Procédé de préparation, d'isolation et de purification de formes pharmaceutiquement applicables de ahu-377 WO2016074651A1 (fr)

Priority Applications (5)

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LTEP15808087.9T LT3218351T (lt) 2014-11-14 2015-11-11 Ahu-377 farmaciniu požiūriu priimtinų formų gavimo, atskyrimo ir gryninimo būdas
PL15808087T PL3218351T3 (pl) 2014-11-14 2015-11-11 Sposób wytwarzania, wyodrębniania i oczyszczania farmaceutycznie dopuszczalnych postaci AHU-377
ES15808087T ES2745157T3 (es) 2014-11-14 2015-11-11 Un método para la preparación, aislamiento y purificación de formas farmacéuticamente aplicables de AHU-377
EP15808087.9A EP3218351B1 (fr) 2014-11-14 2015-11-11 Procédé de préparation, d'isolation et de purification de formes pharmaceutiquement applicables de ahu-377
DK15808087.9T DK3218351T3 (da) 2014-11-14 2015-11-11 Fremgangsmåde til fremstilling, isolering og oprensning af farmaceutisk anvendelige former af ahu-377

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CZPV2014-792 2014-11-14
CZ2014-792A CZ2014792A3 (cs) 2014-11-14 2014-11-14 Způsob přípravy, izolace a čištění farmaceuticky využitelných forem AHU-377
CZ2015-758A CZ2015758A3 (cs) 2015-10-27 2015-10-27 Pevné formy vápenaté soli ethyl esteru (2R, 4S)-5-(bifenyl-4-yl)-4-[(3-karboxypropionyl)amino]-2-methylpentanové kyseliny, způsob jejich přípravy a použití
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CN106496055A (zh) * 2016-10-09 2017-03-15 杭州科巢生物科技有限公司 一种抗心衰新药的关键组分沙库比曲的新合成方法
WO2017097275A1 (fr) * 2015-12-11 2017-06-15 Zentiva, K.S. Formes solides d'ester éthylique d'acide (2r,4s)-5-(biphényl-4-yl)-4-[(3-carboxypropionyl)amino]-2-méthylpentanoïque, ses sels et son procédé de préparation
CN107188817A (zh) * 2017-05-22 2017-09-22 杭州瑞法康科技有限公司 一种高纯度沙库比曲半钙盐一水合物的新晶型及其制备方法
CN107602410A (zh) * 2017-09-13 2018-01-19 浙江三门恒康制药有限公司 沙库比曲钠盐的晶型ii及其制备方法
WO2018040065A1 (fr) * 2016-09-02 2018-03-08 诺瑞特国际药业股份有限公司 Formes cristallines de sel disodique de valsartan
WO2018045505A1 (fr) * 2016-09-07 2018-03-15 诺瑞特国际药业股份有限公司 Nouvelle forme cristalline de sel de sodium de sacubitril
WO2018069833A1 (fr) * 2016-10-10 2018-04-19 Laurus Labs Limited Forme amorphe stable d'un complexe de sacubitril-valsartan trisodique et ses procédés de préparation
WO2018078592A1 (fr) * 2016-10-28 2018-05-03 Biocon Limited Sacubitril/valsartan trisodique amorphe et son procédé de préparation
US11786498B2 (en) 2015-07-02 2023-10-17 Novartis Ag Sacubitril calcium salts

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US11786498B2 (en) 2015-07-02 2023-10-17 Novartis Ag Sacubitril calcium salts
WO2017097275A1 (fr) * 2015-12-11 2017-06-15 Zentiva, K.S. Formes solides d'ester éthylique d'acide (2r,4s)-5-(biphényl-4-yl)-4-[(3-carboxypropionyl)amino]-2-méthylpentanoïque, ses sels et son procédé de préparation
CN109641856A (zh) * 2016-09-02 2019-04-16 诺瑞特国际药业股份有限公司 缬沙坦二钠盐的晶型
WO2018040065A1 (fr) * 2016-09-02 2018-03-08 诺瑞特国际药业股份有限公司 Formes cristallines de sel disodique de valsartan
CN109641856B (zh) * 2016-09-02 2022-09-30 南京诺瑞特医药科技有限公司 缬沙坦二钠盐的晶型
US10745363B2 (en) 2016-09-02 2020-08-18 Nanjing Noratech Pharmaceuticals Co., Ltd Crystal forms of valsartan disodium salt
US10683260B2 (en) 2016-09-07 2020-06-16 Nanjing Noratech Pharmaceuticals Co., Ltd. Crystalline form of sacubitril sodium salt
WO2018045505A1 (fr) * 2016-09-07 2018-03-15 诺瑞特国际药业股份有限公司 Nouvelle forme cristalline de sel de sodium de sacubitril
CN109661386A (zh) * 2016-09-07 2019-04-19 诺瑞特国际药业股份有限公司 沙库比曲钠盐新晶型
CN106496055A (zh) * 2016-10-09 2017-03-15 杭州科巢生物科技有限公司 一种抗心衰新药的关键组分沙库比曲的新合成方法
US11318116B2 (en) * 2016-10-10 2022-05-03 Laurus Labs Limited Stable amorphous form of sacubitril valsartan trisodium complex and processes for preparation thereof
WO2018069833A1 (fr) * 2016-10-10 2018-04-19 Laurus Labs Limited Forme amorphe stable d'un complexe de sacubitril-valsartan trisodique et ses procédés de préparation
JP2020503257A (ja) * 2016-10-28 2020-01-30 バイオコン・リミテッド アモルファスサクビトリルバルサルタン三ナトリウムおよびその調製のためのプロセス
WO2018078592A1 (fr) * 2016-10-28 2018-05-03 Biocon Limited Sacubitril/valsartan trisodique amorphe et son procédé de préparation
US10995060B2 (en) 2016-10-28 2021-05-04 Biocon Limited Amorphous Trisodium Sacubitril Valsartan and process for its preparation
JP7022747B2 (ja) 2016-10-28 2022-02-18 バイオコン・リミテッド アモルファスサクビトリルバルサルタン三ナトリウムおよびその調製のためのプロセス
US11629120B2 (en) 2016-10-28 2023-04-18 Biocon Limited Trisodium sacubitril valsartan and process for its preparation
CN107188817A (zh) * 2017-05-22 2017-09-22 杭州瑞法康科技有限公司 一种高纯度沙库比曲半钙盐一水合物的新晶型及其制备方法
CN107602410A (zh) * 2017-09-13 2018-01-19 浙江三门恒康制药有限公司 沙库比曲钠盐的晶型ii及其制备方法

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LT3218351T (lt) 2019-09-25
HUE046278T2 (hu) 2020-02-28
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EP3218351B1 (fr) 2019-06-19

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